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  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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Definitions

• the present invention relates to the treatment of solid tumors in humans such as cancer, which involves the administration of [6R]-5,10-methylene tetrahydrofolate (6R- MTHF) in 5-fluorouracil (5-FU) based chemotherapy.
• 5-Fluorouracil was first introduced in 1957 and remains a mainstay in treatment of solid tumors including colorectal cancer (CRC).
• 5-FU exerts cytotoxic activity primarily through inhibition of thymidylate synthase (TS) and to some extent also through incorporation of metabolites into RNA.
• TS thymidylate synthase
• the overall response rate of 5-FU alone is quite limited (10-15 %) and modulation strategies have been developed to increase the anticancer activity of 5-FU.
• LV stabilizes the ternary complex that inhibits thymidylate synthase (TS), an enzyme necessary for DNA synthesis.
• TS thymidylate synthase
• a reduced folate, fotrexorin calcium (CoFactor®) ((i//)-5,10,-methylenepteroyl- monoglutamatc calcium salt, or [6R,S]-5,10-methylene-THF Ca salt), also known as racemic methyleneTHF, has been suggested as an alternative to LV based on the assumption that direct administration of the reduced folate methyleneTHF in place of LV might offer significant advantages with respect to clinical activity.
• CoFactor® is a 1:1 mixture of the two diastercoisomers (Odin, E., Carlsson, G., Frosing, R., Gustavsson, B., Spears, CP., Larsson, P.A., 1998.
• the unnatural (6S)-isomer is a partial competitive inhibitor of the natural [6R]-isomer regarding its effect as co-substrate for TS (Leary, R.P., Gaumont, Y., Kisliuk, R.L., 1974. Effects of the diastereoisomers of methylenetetrahydrofolate on the reaction catalyzed by thymidylate synthetase. Biochem. Biophys. Res. Commun. 56, 484-488).
• the inventors have discovered that equimolar doses of 6R-MTHF surprisingly produces significantly higher levels of dUrd in blood plasma compared to with LV when coadministered with 5-FU.
• the elevation of plasma 2'-deoxyuridine (dUrd) is a marker of TS inhibition.
• the present invention surprisingly provides methods for increasing plasma dUrd levels comprising the administration of 6R-MTHF.
• the methods of increasing plasma dUrd increase levels compared to equimolar concentrations of LV.
• the present invention also provides methods for increasing TS inhibition comprising the administration of 6R-MTHF.
• Plasma dUrd elevation as a surrogate marker of TS-inhibition has progressively become the biomarker of choice.
• the analysis is also relatively simple to perform, by blood sampling and LC-MS/MS analysis.
• Treatment with TS inhibitors like 5-FU, causes a rise in intracellular pools of the TS substrate dUMP, which is reflected in raised levels of the corresponding nucleoside dUrd, which is largely extracellular and can be measured in the plasma.
• elevations of plasma dUrd have been shown to follow administration of TS inhibitors, and is thus a surrogate marker of TS inhibition (Ford et al (2002)).
• the elevation of plasma dUrd levels is understood by the inventors to directly mirror the current integrated tumor TS-inhibitory state in the body during 5-FU treatment, reflecting all existing tumor sites including metastases.
• the plasma dUrd level as a surrogate marker for TS inhibition clearly stands out against older assays based on e.g. 3 H-FdUMP TS-binding, which are only confined to in vitro studies of e.g. biopsies of tumors or mucosa, or of isolated TS-enzyme.
• These radiolabel- based binding assays are today rarely if ever used and are strongly associated with very large degrees of variation (Peters et al. (1991) Eur J Cancer, 27(3): 263-267) as well as difficulties to get hold of necessary materials for the assays.
• Fig. 1 Increased TS inhibition following administration of 5-FU with 30 and 60 mg/m 2 6R-MTHF (denoted as “6R”) compared to 30 mg/m 2 1-LV (“LLV”) (denoted as “LLV 30”) compare to 60 mg/m 2 racemic (d,l-LV or LV).
• Fig. 2 Plasma dUrd levels relative to 30 mg/m 2 LLV (60 mg/m 2 of d,l-LV or LV or LV 60) following administration of 5-FU with 30 and 60 mg/m 2 6R-MTHF (denoted as "6R").
• Fig. 3 Equimolar comparison of LV and 6R-MTHF shown as incremental plasma dUrd levels at 24 hours after bolus injection of 5-FU 500 mg/m 2 administered together with bolus injection of 30 mg/m 2 of 1-LV (denoted as "LLV30") (60 mg/m 2 of d,l-LV or LV) or 30 mg/m 2 of 6R-MTHF (denoted as "M30").
• LLV30 1-LV
• M30 30 mg/m 2 of 6R-MTHF
• LLV is the active natural isomer of LV which is a 50:50 mixture of LLV and the unnatural, not (significantly) active d-LV.
• the molecular weights of 6R-MTHF and LLV are sufficiently similar as basis for an equimolar comparison. The difference between the group has been tested with the Mann-Whitney U test (p ⁇ 0.05).
• Fig. 4 6R-MTHF dose dependent increase of incremental plasma dUrd levels at 24 hours after bolus injection of 5-FU 500 mg/m 2 administered together with bolus injection of 30 mg/m 2 LLV (denoted as "LLV30”) (60 mg/m 2 of d,l-LV or LV) or 30 mg/m 2 (denoted as "M30”) or 60 mg/m 2 of 6R-MTHF (denoted as "M60").
• [6R]-5,10-methylenetetrahydrofolic acid (6R-MTHF) or a pharmaceutically acceptable salt thereof is employed as a solid form which is soluble in water or as a lyophilisate, optionally stabilized by one or more suitable excipients and/or antioxidants such as citric acid or ascorbic acid or salt forms thereof.
• 6R- MTHF is administered as one or more IV boluses, each bolus containing 5 - 1000 mg/m 2 BSA (body surface area), such as 5 mg/m 2 BSA, such as 7 mg/m 2 BSA, such as 10 mg/m 2 BSA, such as 15 mg/m 2 BSA, such as 30 mg/m 2 BSA, such as 60 mg/m 2 BSA, such as 120 mg/m 2 BSA, such as 240 mg/m 2 BSA, such as 480 mg/m 2 BSA, such as 720 mg/m 2 BSA or such as 960 mg/m 2 BSA.
• “bolus” means a method of intravenous
• a single dose of a pharmaceutical composition is given all at once, unlike intravenous infusion wherein a single dose is given over at constant concentration over a period of time.
• the dosage depends on the form of therapy, on the form of application of the preparation, and on the age, weight, nutrition and condition of the patient. Treatment can commence with a smaller amount, below the optimum amount, which can be increased in order to achieve the optimum effect.
• the preferred dose used in therapy ranges between 10 mg and 3,000 mg per day, particularly between 50 mg and 500 mg per day. Administration can be effected either as a single dose or as a repeated dose.
• 6R-MTHF may be in the form of a free acid, in the form of pharmaceutically acceptable salts, particularly acidic salts, as well as alkali or alkaline earth metal salts.
• MTHF comprises both diastereomeric isomers, particularly diastereoisomerically pure, natural 6R-MTHF.
• diastereoisomerically pure means 6R-MTHF or its salt in isomeric excess over the other isomer greater than about 80%, preferably greater than about 90%, preferably greater than about 95%, more preferably greater than about 97%, even more preferably greater than about 99%, more preferably greater than about 99.5% or more, and most preferably up to 100%, wherein the remainder is the other isomer 6S-MTHF.
• the 6R-MTHF is chemically pure.
• the term "chemically pure” means a compound in about 80% chemical purity, preferably about 90%, more preferably about 95%, more preferably about 97%, more preferably about 98% chemical purity, and most preferably 99% or higher than 99%, e.g., 99.5, 99.6, 99.7, 99.8, 99.9 or up to 100% chemical purity, as determined by HPLC.
• Chemical impurities may include unreacted starting material (including solvents), degradation products of 6R-MTHF (such as tetrahydrofolic acid and its degradation products), etc.
• a pharmaceutical composition comprising 6R-MTHF may further comprise at least one anticancer compound.
• An anticancer compound may include but is not limited to one or more chemotherapeutic agents, such as but not limited to: nucleic acids, in particular fluorinated nucleic acids (e.g. 5-flurouracil (5-FU) or an analog or prodrug thereof), antifolates (e.g. pemetrexed, raltitrexed, lometrexol), topoisomerase inhibitors (e.g. irinotecan, topotecan), antimetabolite drugs (e.g.
• chemotherapeutic agents such as but not limited to: nucleic acids, in particular fluorinated nucleic acids (e.g. 5-flurouracil (5-FU) or an analog or prodrug thereof), antifolates (e.g. pemetrexed, raltitrexed, lometrexol), topoisomerase inhibitors (e.g. iri
• methotrexate, gemcitabine, tezacitabine 5- FU modulators
• alkylating agents e.g. cyclophosphamide, carmustine
• nucleic acid biosynthesis inhibitors such as mitomycin, anthracyclines (e.g. epirubicin, doxorubicin), platinum derivatives (e.g. cisplatin, oxaliplatin, carboplatin), microtubule disrupting drugs (e.g. paclitaxel, docetaxel, vinolrebine, vincristine), hormone blocking drugs (e.g. tamoxifen), inhibitors of kinases, including but not limited to receptor and nonreceptor tyrosine kinases (e.g.
• Anticancer compounds may also include monoclonal antibodies, such as but not limited to monoclonal antibodies that bind cytokines, hormones, or hormone receptors (e.g.
• the 6R-MTHF is administered in combination with a therapeutically effective amount of at least one anticancer compound.
• a therapeutically effective amount of at least one anticancer compound a person of ordinary skill in the art would understand that the at least one anticancer compound can be administered before, after or concurrently with 6R-MTHF.
• N/A not applicable
• SP2D selected phase 2 dose
• the time-point window for Oxaliplatin administration will be expanded to allow infusion times of up to 120 minutes, if necessary
• the present study is a historical group comparison study. All patients have been treated with a standard dose of 500 mg 5-FU given as a bolus injection plus the respective folate 6R-MTHF or LV also given as bolus injections. 2. Patients treated with 6R-MTHF.
• LV metastatic colorectal cancer
• Plasma dUrd was determined by a method comprising liquid chromatography followed by tandem mass spectrometry broadly summarized as follows. Plasma samples were removed from -80°C freezer, trichloroacetic acid was added to the plasma, and the samples mixed and centrifuged. The supernatant was filtered in a 10 kDa molecular weight cut-off membrane filter and again centrifuged for 30 min. The solution at the bottom of the tube was then ready for LC-MS/MS analysis. Calibration samples were prepared in the same way using blank plasma samples and different internal standard concentrations. The injection volume into LC-MS/MS was 40 ul. Deoxyuridine and chlorodeoxyuridine were ionized by electrospray negative mode. MS parameters were optimized for maximum response of all folates. A MS/MS acquisition method (multiple reaction monitoring) was utilized. EXAMPLE 2 -TS Inhibition.
• the LV bolus dose of 60 mg/m 2 is the standard dose used in the so called Nordic treatment regime used widely in Scandinavia. Clinical results are similar to those obtained with other regimes when LV is administered by infusion, often 400 mg over two hours. 0 (Gustavsson et ah, (2015) Clinical Colorectal Cancer, 14: 1-10). It is interesting to note the much higher TS inhibition after 6R-MTHF ( Figure 2).

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